Crystal forms of thiophene derivatives

ABSTRACT

Disclosed is crystal form II of compound (S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present disclosure claims the benefits of the Chinese patentapplication No. 201810407741.X, entitled “Polymorphs of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl))-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideand its preparation and application” filed on May 2, 2018 before theNational Intellectual Property Administration of the People's Republicof China. The contents of the above-mentioned patent application in itsentirety are incorporated herein by reference.

FIELD

The present disclosure generally relates to the field of organicchemistry and medicinal chemistry.

BACKGROUND

PDE-4 enzyme inhibitors are effective on various inflammatory diseasesin clinical, including asthma, chronic obstructive pulmonary disease(COPD), allergic rhinitis, allergic dermatitis and the like. PDE-4enzyme inhibitors are also effective on various diseases includingarthritis, sepsis and the like on animal models.

SUMMARY

In one aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having characteristic peaks at diffraction angles 2θ of about 8.3°,13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having characteristic peaks at diffraction angles 2θ of 8.3±0.2°,13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2° and24.4±0.2° in an X-ray powder diffraction (XRPD) pattern.

In still another aspect, the present disclosure relates to crystal formII of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,wherein diffraction angle 2θ, crystal plane spacing d and relativeintensity of diffraction peak in an X-ray powder diffraction (XRPD)pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In still yet another aspect, the present disclosure relates to crystalform II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,wherein diffraction angle 2θ, crystal plane spacing d and relativeintensity of diffraction peak in an X-ray powder diffraction (XRPD)pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having an X-ray powder diffraction (XRPD) pattern substantially as shownin FIG. 1.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially free of solvent, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially free of water, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially pure, having characteristic peaks at diffractionangles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and24.4° in an X-ray powder diffraction (XRPD) pattern.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is free of solvent and water, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In yet another aspect, the present disclosure relates to apharmaceutical composition, comprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideand a pharmaceutically acceptable carrier, diluent or excipient, whereinthe crystal form I has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In another aspect, the present disclosure relates to a process forpreparing crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,comprising crystallizing(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidein ethyl acetate to obtain the crystal form II, wherein the crystal formII has characteristic peaks at diffraction angles 2θ of about 8.3°,13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In another aspect, the present disclosure relates to a method fortreating or preventing a disease or condition associated with PDE4enzyme, preferably mediated by PDE4 enzyme, comprising administering atherapeutically effective amount of crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideor a therapeutically effective amount of a pharmaceutical compositioncomprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideto a subject in need thereof, wherein the crystal form I hascharacteristic peaks at diffraction angles 2θ of about 8.3°, 13.8°,14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having characteristic peaks atdiffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°,18.7±0.2°, 21.6±0.2°, 23.1±0.2° and 24.4±0.2° in an X-ray powderdiffraction (XRPD) pattern.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, wherein diffraction angle 2θ, crystalplane spacing d and relative intensity of diffraction peak in an X-raypowder diffraction (XRPD) pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, wherein diffraction angle 2θ, crystalplane spacing d and relative intensity of diffraction peak in an X-raypowder diffraction (XRPD) pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 1.

In another aspect, the present disclosure relates to a method forreducing PDE4 activity, comprising administering a therapeuticallyeffective amount of crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideor a therapeutically effective amount of a pharmaceutical compositioncomprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideto a subject in need thereof, wherein the crystal form I hascharacteristic peaks at diffraction angles 2θ of about 8.3°, 13.8°,14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystal formII of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure.

FIG. 2 shows a differential scanning calorimetry (DSC) curve of crystalform II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure.

FIG. 3 shows a thermogravimetric analysis (TGA) curve of crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure.

FIG. 4 shows an infrared (IR) spectroscopy of crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide of the present disclosure.

FIG. 5 shows a DSC curve of crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure after compressed into a tablet.

DETAILED DESCRIPTION

In the following description, certain specific details are included toprovide a thorough understanding of the various disclosed embodiments.One skilled in the relevant art will recognize, however, thatembodiments may be practiced without one or more of these specificdetails, with other methods, components, materials, etc.

Unless the context required otherwise, throughout the specification andclaims which follows, the term “comprise” and variations thereof, suchas “comprises” and “comprising” are to be construed in an open,inclusive sense, which is as “include, but not limited to”.

As used herein and the appended claims when in use, unless the contextclearly dictates otherwise, it is not singular forms include pluralreferents with a number indicated.

Reference throughout this specification to “one embodiment”, or “anembodiment”, or “in another embodiment”, or “in some embodiments” meansthat a particular referent feature, structure or characteristicdescribed in connection with the embodiments is included in at least oneembodiment. Therefore, the appearance of the phrases “in oneembodiment”, or “in the embodiment”, or “in another embodiment”, or “insome embodiments” in various places throughout this specification arenot necessarily all referring to the same embodiment. Moreover, theparticular features, structures or characteristics may be combined inany suitable manner in one or more embodiments.

It is to be understood that the singular forms of articles “a”, “an” and“the” as used in the specification and the appended claims of thepresent disclosure include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to a pharmaceuticalcomposition comprising a “pharmaceutically acceptable carrier, diluent,or excipient” includes one pharmaceutically acceptable carrier, diluentor excipient, or two or more pharmaceutically acceptable carriers,diluents or excipients.

Definition

Therefore, unless otherwise indicated, the following terms used in thespecification and the appended claims have the following meanings:

In the present disclosure, the term “compound of the present disclosure”refers to(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,which has the structure as shown below:

As used herein, the use of the term “about” includes and describesvalues or parameters per se. For example, “about X” includes anddescribes “X” itself. In some embodiments, the term “about” refers to achange of +/−5% when used in conjunction with or for modifying values,units, constants or numerical ranges.

As used herein, when referring to an X-ray powder diffraction (XRPD)pattern, a differential scanning calorimetry (DSC) curve, athermogravimetric analysis (TGA) curve, an infrared (IR) spectroscopy.the term “substantially as shown in” does not necessarily refer to thesame pattern and curve as those depicted in the present disclosure, butfalls within the limits of experimental error or deviation whenconsidered by one skilled in the art.

As used herein, the term “essentially identical” with reference to X-raydiffraction peak positions means that typical peak position andintensity variability are taken into account. For example, one skilledin the art will appreciate that the peak positions (2θ) will show somevariability, typically as much as 0.1 to 0.2 degrees, depending on thesolvents being used, as well as on the apparatus being used to measurethe diffraction. Further, one skilled in the art will appreciate thatrelative peak intensities will show inter-apparatus variability as wellas variability due to degree of crystallinity, preferred orientation,prepared sample surface, and other factors known to those skilled in theart, and should be taken as qualitative measures only.

As used herein, the term “2θ value” or “2θ” refers to the peak positionin degrees based on the experimental setup of the X-ray diffractionexperiment and is a common abscissa unit in diffraction patterns. Theexperimental setup requires that if a reflection is diffracted when theincoming beam forms an angle theta (θ) with a certain lattice plane, thereflected beam is recorded at an angle 2 theta (2θ). It should beunderstood that reference herein to specific 2θ values for a specificpolymorphic form is intended to mean the 2θ values (in degrees) asmeasured using the X-ray diffraction experimental conditions asdescribed herein. For example, as described herein, CuKa (λ−1.54056 Å)was used as the source of radiation.

As used herein, In order to lattice spacing (d-spacing) of the object,the term “about” refers to ±0.1 Å.

As used herein, the term “substantially pure” refers to chemical purityand crystalline purity.

As used herein, the term “substantially free” refers to containing notmore than about 20% by weight. For example, substantially free ofsolvent refers to containing not more than about 20% by weight ofsolvent. Substantially free of water refers to containing not more than20% by weight of water.

As used herein, the term “mammal” means animals including, for example,dogs, cats, cows, sheep, horses, and humans. In some embodiments,mammals include humans.

As used herein, the term “patient” means an animal, such as a human, acompanion animal, such as a dog, cat and horse, and livestock, such ascattle, swine and sheep. In some embodiments, patients are mammals,including both males and females. In some embodiments, patients arehumans.

As used herein, the term “pharmaceutically acceptable” as used hereinmeans the carrier, vehicle, diluent, excipient and/or salt must becompatible with the other ingredients of the formulation, and notdeleterious to the recipient thereof. other ingredients of theformulation and will not be detrimental to its recipient.

As used herein, the term “pharmaceutically acceptable carrier, diluentor excipient” includes without limitation any adjuvant, carrier,excipient, glidant, sweetening agent, diluent, preservative,dye/colorant, flavor enhancer, surfactant, wetting agent, dispersingagent, suspending agent, stabilizer, isosmotic agent, solvent, oremulsifier, etc, which has been approved by the United States Food andDrug Administration as being acceptable for use in humans or animals andhave no side effects on preparing a pharmaceutical composition.

As used herein, the term “carrier” defines a compound that facilitatesthe incorporation of a crystal form of a compound into cells or tissues.For example, dimethylsulfoxide (DMSO) is generally used as a carrier, asit facilitates the uptake of many organic compounds into cells ortissues of an organism.

As used herein, the term “pharmaceutical composition” refers to aformulation of crystal II of the compound in the present disclosure anda medium generally acceptable in the art for the delivery of thebiologically active compound to mammals, e.g., humans. Such a mediumincludes all pharmaceutically acceptable carriers, diluents orexcipients therefor.

As used herein, the term “therapeutically effective amount” refers to anamount of crystal form II of the compound or combination of crystal formII that ameliorates, attenuates or eliminates a particular disease orcondition or a symptom of a particular disease or condition, or preventsor delays the onset of a particular disease or condition or a symptom ofa particular disease or condition. The amount of crystal form II of thecompound of the present disclosure which constitutes a “therapeuticallyeffective amount” will vary depending on crystal form II of thecompound, the condition and its severity, and the age of the mammal tobe treated, but can be determined routinely by one of ordinary skill inthe art having regard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, such as a human, havingthe disease or disorder of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment; or

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

As used herein, the term “physiologically acceptable” refers to acarrier or diluent that does not eliminate the biological activities andproperties of a compound.

Specific Embodiments

In one aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having characteristic peaks at diffraction angles 2θ of about 8.3°,13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehas characteristic peaks at diffraction angles 2θ of about 8.3°, 13.8°,14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern under CuKα radiation.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having characteristic peaks at diffraction angles 2θ of 8.3±0.2°,13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2° and24.4±0.2° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehas characteristic peaks at diffraction angles 2θ of 8.3±0.2°,13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°, 23.1±0.2° and24.4±0.2° in an X-ray powder diffraction (XRPD) pattern under CuKαradiation.

In still another aspect, the present disclosure relates to crystal formII of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,wherein diffraction angle 2θ, crystal plane spacing d and relativeintensity of diffraction peak in an X-ray powder diffraction (XRPD)pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In some embodiments, diffraction angle 2θ, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern under CuKα radiation of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4c]pyrrole-1-yl]acetamideare about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In still yet another aspect, the present disclosure relates to crystalform II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,wherein diffraction angle 2θ, crystal plane spacing d and relativeintensity of diffraction peak in an X-ray powder diffraction (XRPD)pattern are about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In some embodiments, diffraction angle 2θ, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern under CuKα radiation of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideare about as follows:

2θ Crystal Plane Intensity (°) Spacing d (Å) (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having an X-ray powder diffraction (XRPD) pattern substantially as shownin FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehas an X-ray powder diffraction (XRPD) pattern under CuKα radiationsubstantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least one characteristic peak in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least two characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least three characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least four characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least five characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least six characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least seven characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least eight characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least nine characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least ten characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least eleven characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least twelve characteristic peaks in an X-ray powder diffraction(XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least thirteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least fourteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least fifteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least sixteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least seventeen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least eighteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an X-ray powder diffraction (XRPD) patternwith at least nineteen characteristic peaks in an X-ray powderdiffraction (XRPD) pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at about 174.2° C.when subjected to thermal analysis using differential scanningcalorimetry (DSC).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at about 174.2° C.when subjected to thermal analysis using differential scanningcalorimetry (DSC) at a heating rate of 10° C./min.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±6° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±4° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±2° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±6° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC) at a heating rate of 10° C./min.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±4° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC) at a heating rate of 10° C./min.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an endothermic peak at 174.2±2° C. whensubjected to thermal analysis using differential scanning calorimetry(DSC) at a heating rate of 10° C./min.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has a DSC curve substantially as shown in FIG.2 when subjected to thermal analysis using differential scanningcalorimetry (DSC).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has a DSC curve substantially as shown in FIG.2 when subjected to thermal analysis using differential scanningcalorimetry (DSC) at a heating rate of 10° C./min.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has a TGA curve substantially as shown in FIG.3 when subjected to thermal analysis using thermogravimetric analysis(TGA).

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has a TGA curve substantially as shown in FIG.3 when subjected to thermal analysis using thermogravimetric analysis(TGA) at a heating rate of 10° C./min.

In some embodiments, position and intensity of absorption peak of thecrystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure in an infrared (IR) spectroscopy are about asfollows:

Position of Intensity of Absorption Peak (cm⁻¹) Absorption Peak (%)3453.2 70.26 3241.43 48.73 3180.17 71.75 3083.24 76.81 3027.45 63.763006.17 61.87 2984.61 66.79 2957.88 66.9 2929.86 60.24 2874.13 72.922838.3 73.97 1762.16 35.25 1711.28 6.93 1696.91 16.68 1589.87 17.991556.49 32.02 1519.41 25.37 1501.04 44.56 1474.83 62.39 1462.27 64.911444.23 64.41 1434.62 58.52 1392.39 41.14 1370.64 49.6 1334.38 20.751290.88 11.9 1261.44 22.72 1239.78 16.73 1186.33 72.49 1165.47 65.761139.31 19.78 1090.26 28.34 1041.96 50.12 1024.97 51.39 1013.68 54.36987.29 69.86 974.97 54.3 893.33 61.77 884.21 86.94 853.9 63.5 821.4174.9 807.59 77.16 772.11 68.12 763.87 64.75 733.78 56.35 717.63 35.54698.77 65.19 645.374 65.19 605.85 69.96 582.92 80.93 560.18 81.03 538.8163.92 526.24 69.09 511.55 77.6 485.9 62.86 453.09 63.17

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure has an infrared (IR) spectroscopysubstantially as shown in FIG. 4.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure compared with other solid forms has at leastone advantageous property: chemical purity, fluidity, solubility,dissolution rate, morphology or crystal habit, stability such as hightemperature stability, accelerated stability, illumination stability,grinding stability, pressure stability, stability in ethanol solutionafter equilibrium, stability in aqueous solution after equilibrium, lowresidual solvent content, lower hygroscopicity, fluidity, and favorableprocessing and treatment properties such as compressibility and bulkdensity.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially free of solvent, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat substantially free of solvent has characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern under CuKαradiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 20% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 20% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 10% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 10% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 5% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 5% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 3% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 3% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 1% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 1% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.5% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.5% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.2% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.2% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.1% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.1% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.01% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.01% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.001% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.001% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.0001% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.0001% byweight of solvent has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is free of solvent has characteristic peaks at diffraction angles2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° inan X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is free of solvent has characteristic peaks at diffraction angles2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° inan X-ray powder diffraction (XRPD) pattern under CuKα radiation.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially free of water, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially free of water has characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern under CuKαradiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 20% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 20% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 10% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 10% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 5% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 5% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 3% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 3% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 1% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 1% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.5% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.5% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.2% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.2% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.1% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.1% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.01% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.01% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.001% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.001% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.0001% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that comprises not more than about 0.0001% byweight of water has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that is free of water has characteristic peaksat diffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°,21.6°, 23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that is free of water has characteristic peaksat diffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°,21.6°, 23.1° and 24.4° in an X-ray powder diffraction (XRPD) patternunder CuKα radiation.

In some embodiments, weight loss of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure is not more than 5.0% when the crystal form IIis heated to melt during thermal analysis using thermogravimetricanalysis (TGA) at a heating rate of 10° C./min. No absorption/exothermicpeak is located before melting. Therefore, the weight loss of not morethan 5.0% is adsorbed water or solvent.

In some embodiments, weight loss of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure is not more than 3.0% when the crystal form IIis heated to melt during thermal analysis using thermogravimetricanalysis (TGA) at a heating rate of 10° C./min. No absorption/exothermicpeak is located before melting. Therefore, the weight loss of not morethan 3.0% is adsorbed water or solvent.

In some embodiments, weight loss of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure is not more than 2.0% when the crystal form IIis heated to melt during thermal analysis using thermogravimetricanalysis (TGA) at a heating rate of 10° C./min. No absorption/exothermicpeak is located before melting. Therefore, the weight loss of not morethan 2.0% is adsorbed water or solvent.

In some embodiments, weight loss of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure is not more than 1.0% when the crystal form IIis heated to melt during thermal analysis using thermogravimetricanalysis (TGA) at a heating rate of 10° C./min. No absorption/exothermicpeak is located before melting. Therefore, the weight loss of not morethan 1.0% is adsorbed water or solvent.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is substantially pure, having characteristic peaks at diffractionangles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that is substantially pure has characteristicpeaks at diffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°,18.7°, 21.6°, 23.1° and 24.4° in an X-ray powder diffraction (XRPD)pattern under CuKα radiation.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that is substantially pure comprises at leastabout 95% by weight, preferably at least about 98% by weight, morepreferably at least about 99% by weight of the crystal form II and lessthan about 5% by weight, preferably less than about 2% by weight, morepreferably less than about 1% by weight of other compounds havingstructures different from the chemical structure of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure that is substantially pure comprises at leastabout 95% by weight, preferably at least about 98% by weight, morepreferably at least about 99% by weight of the crystal form II and lessthan about 5% by weight, preferably less than about 2% by weight, morepreferably less than about 1% by weight of other crystal forms ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure. This means the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof the present disclosure comprises less than about 5% by weight ofother compounds and less than about 5% by weight of any other forms(also referred to as “phase uniformity”).

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is free of solvent and water, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidethat is free of solvent and water has characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern under CuKαradiation.

In yet another aspect, the present disclosure relates to apharmaceutical composition comprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideand a pharmaceutically acceptable carrier, diluent or excipient, whereinthe crystal form I has characteristic peaks at diffraction angles 2θ ofabout 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in anX-ray powder diffraction (XRPD) pattern.

In some embodiments, the pharmaceutical composition of the presentdisclosure is formulated as tablet, solution, granule, patch, ointment,gel, capsule, aerosol or suppository administered via parenteral,transdermal, mucosa, nasal, buccal, sublingual or oral route.

Pharmaceutical Composition

In some embodiments, the pharmaceutical composition comprises crystalform II of the compound as disclosed herein, and a pharmaceuticallyacceptable carrier, diluent, or excipient.

In some embodiments, the route of administration of the crystal form IIfor treating or preventing a disease associated with PDE4 enzyme,preferably mediated by PDE4 enzyme to the mammals can be non-parenteralroute.

In some embodiments, the route of administration of the crystal form IIfor treating or preventing a disease associated with PDE4 enzyme,preferably mediated by PDE4 enzyme to the mammals can be oral route.

In some embodiments, the route of administration of the crystal form IIfor treating or preventing a disease associated with PDE4 enzyme,preferably mediated by PDE4 enzyme to the mammals can be intrarectalroute.

The compound as described herein may be obtained in any suitable formsuch as tablet, capsule, powder, oral solution, suspension, patch,ointment, gel, capsule, aerosol, suppository and the like. Exemplaryexamples of tablets comprise, but are not limited to, plain tablets,sugar-coated tablets and film-coated tablets.

Examples of a pharmaceutically acceptable carrier that can be used inthe pharmaceutical composition of the present disclosure include, butare not limited to, any adjuvant, carrier, excipient, glidant,sweetening agent, diluent, preservative, dye/colorant, flavor enchancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isosmotic agent, solvent or emulsifier, which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or animals. Acceptable carriers or diluentsfor therapeutic use are well-known in the art, and are described, forexample, in Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing Co., Easton, Pa. (1990), which is incorporated herein byreference in its entirety.

The pharmaceutical compositions of the present disclosure may beadministered by any means that achieve their intended purpose. Forexample, administration may be by oral, parenteral, topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal,transdermal, or buccal routes. The route of administration can benon-parenteral route, oral route and intrarectal route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art.

Particularly suitable for oral use are ordinary tablets (plain tablets),sugar-coated tablet, film-coated tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,or oil-based or aqueous solutions, furthermore suspensions, emulsions orimplants, and suitable for topical use are ointments, creams or powders.The compounds of the present disclosure may also be lyophilised and theresultant lyophilisates used, for example, for the preparation ofinjection preparations. The preparations indicated may be sterilisedand/or comprise assistants, such as lubricants, preservatives,stabilisers and/or wetting agents, emulsifiers, salts for modifying theosmotic pressure, buffer substances, dyes, flavours and/or a pluralityof further active ingredients, for example one or more vitamins.

In some embodiments, a pharmaceutical composition of the presentdisclosure is formulated as tablet, solution, granule, patch, ointment,capsule, aerosol or suppository administered via parenteral,transdermal, mucosa, nasal, buccal, sublingual or oral route.

Preservatives, stabilizers, dyes, sweeteners, flavoring agents,fragrances, and the like, may be provided in the pharmaceuticalcomposition. For example, sodium benzoate, ascorbic acid and esters ofp-hydroxybenzoic acid may be added as preservatives. Furthermore,antioxidants and suspending agents may be used.

In various embodiments, alcohols, esters, sulfating aliphatic alcohols,and the like may be used as surfactants; sucrose, glucose, lactose,starch, crystalline cellulose, mannitol, light anhydrous silicate,magnesium aluminate, methyl magnesium silicate aluminate, syntheticaluminum silicate, calcium carbonate, calcium bicarbonate, calciumhydrogenphosphate, calcium hydroxymethyl cellulose and the like may beused as excipients; magnesium stearate, talc, hardened oil may be usedas smoothing agents; coconut oil, olive oil, sesame oil, peanut oil,soybean may be used as suspending agents or lubricants; celluloseacetate phthalate as a derivative of a carbohydrate such as cellulose orsugar, or methylacetate-methacrylate copolymer as a derivative ofpolyethylene may be used as suspending agents; and plasticizers such asester phthalates and the like may be used as suspending agents.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, topical, or intestinal administration; parenteraldelivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal or intraocular injections.The compound can be administered in sustained or controlled releasedosage forms, including depot injections, osmotic pumps, pills,transdermal (including electromigrating) patches, and the like forprolonged and/or timed, pulsed administration at a predetermined rate.

Pharmaceutical compositions of the present disclosure may be manufacturein manner that is itself known, for example, by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or tabletting processes.

Pharmaceutical compositions for use in accordance with the presentdisclosure thus may be formulated by a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing the active compounds intopreparation which can be used pharmaceutically. Proper formulation isdependent on the route of administration chosen. Any of the well-knowntechniques, carriers and excipients may be used as suitable and asunderstood in the art.

Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, glucose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, and thelike. Furthermore, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like.Physiologically compatible buffers include, but are not limited to,Hank's solution, Ringer's solution or physiological saline buffer. Ifdesired, absorption enhancing preparations (such as liposomes) may beused.

For oral administration, the compound can be formulated readily bycombining the active compound with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compound of thedisclosure to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, ointments, suspensions, and the like, for oralingestion by a patient to be treated. Pharmaceutical preparation fororal use can be obtained by combining the active compound with solidexcipient, optionally grinding a resultant mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, saccharose, mannitol orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the crosslinkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate. Dragee cores are provided with suitable coatings. Forthis purpose, concentrated sugar solutions may be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solution, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added into the tablets or dagree coatings for identification or tocharacterizing different combinations of active compound doses. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solution, andsuitable organic solvents or solvent mixtures.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain active ingredients in admixture with filler such assugar, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive ingredients may be dissolved or suspended in suitable liquids,such as fatty oil, liquid paraffin, or liquid polyethylene glycols.Furthermore, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for such administration.

In some embodiments, the pharmaceutical composition of the presentdisclosure may comprise 0.1%-95% of the crystal form II of the compoundas disclosed herein.

In some embodiments, the pharmaceutical composition of the presentdisclosure may comprise 1%-70% of the crystal form II of the compound asdisclosed herein.

Under any circumstances, the composition or formulation to beadministered may comprise some amount of the crystal form II of thecompound as disclosed herein, which is effective to treat thedisease/condition of a study subject to be treated.

In another aspect, the present disclosure relates to a process forpreparing crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,comprising crystallizing(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidein ethyl acetate to obtain the crystal form I, wherein the crystal formI has characteristic peaks at diffraction angles 2θ of about 8.3°,13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In some embodiments,(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideis dissolved in ethyl acetate until completely dissolved and isfiltered. The filtrate is heated to 60° C. to precipitate the crystalform II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

In some embodiments,(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideis dissolved in ethyl acetate and stirred at the room temperature untilcompletely dissolved. The mixture is heat filtered. The filtrate isheated to 50° C. to 70° C. and evaporated at the same temperature underthe atmospheric pressure to precipitate crystalline powders. The powdersare filtered and dried in vacuo to obtain the crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

In some embodiments,(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideis dissolved in ethyl acetate and stirred at the room temperature untilcompletely dissolved. The mixture is heat filtered. The filtrate isheated to 60° C. and evaporated at the same temperature under theatmospheric pressure to precipitate crystalline powders. The powders arefiltered and dried in vacuo to obtain the crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

In another aspect, the present disclosure relates to a method fortreating or preventing a disease or condition associated with PDE4enzyme, preferably mediated by PDE4 enzyme, comprising administering atherapeutically effective amount of crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideor a therapeutically effective amount of a pharmaceutical compositioncomprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideto a subject in need thereof, wherein the crystal form I hascharacteristic peaks at diffraction angles 2θ of about 8.3°, 13.8°,14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

In some embodiments, the subject is a mammal.

In some embodiments, the subject is a human.

Exemplary examples of diseases or conditions that can be used in thepresent disclosure include, but are not limited to, inflammatorydiseases or conditions, infectious diseases or conditions, immunologicaldiseases or conditions, and cancer diseases or conditions.

In some embodiments, exemplary examples of the diseases or conditionsinclude, but are not limited to, head carcinoma, thyroid carcinoma, neckcancer, eye cancer, skin cancer, oral cancer, throat cancer, esophaguscancer, breast cancer, bone cancer, leukemia, myeloma, lung cancer,colon cancer, carcinoma of sigmoid, rectal cancer, gastric cancer,prostate cancer, breast cancer, ovarian cancer, kidney cancer, livercancer, pancreatic cancer, brain cancer, intestinal cancer, heartcancer, adrenal carcinoma, subcutaneous tissue cancer, lymph nodecancer, malignant melanoma, malignant glioma, HIV, hepatitis, adultrespiratory distress syndrome, bone absorption disease, chronicobstructive pulmonary disease, chronic pneumonia, dermatitis,inflammatory skin disease, atopic dermatitis, cystic fibrosis, septicshock, pyaemia, endotoxin shock, blood dynamic shock, septic diseasesyndrome, ischemia reperfusion injury, meningitis, psoriasis, fibrosisdisease, cachexia, graft rejection of graft versus host disease,autoimmunity disease, rheumatoid spondylitis, arthritis symptom (such asrheumatoid arthritis or osteoarthritis), osteoporosis, Crohn's disease,ulcerative colitis, enteritis, multiple sclerosis, systemic lupuserythematosus, erythema nodosum leprosum of leprosy (ENL), radiationdamage, asthma, oxygen enriched lung injury, microorganism infectionsand microorganism infection syndrome.

In some embodiments, a method for treating or preventing a disease orcondition associated with PDE4 enzyme, preferably mediated by PDE4enzyme, comprising administering 1 mg to 10 g of the crystal form II ofthe compound as disclosed herein to a subject in need thereof.

In some embodiments, a method for treating or preventing a disease orcondition associated with PDE4 enzyme, preferably mediated by PDE4enzyme, comprising administering 10 mg to 3000 mg of the crystal form IIof the compound as disclosed herein to a subject in need thereof.

In some embodiments, a method for treating or preventing a disease orcondition associated with PDE4 enzyme, preferably mediated by PDE4enzyme, comprising administering 1 mg to 200 mg of the crystal form IIof the compound as disclosed herein to a subject in need thereof.

In some embodiments, a method for treating or preventing a disease orcondition associated with PDE4 enzyme, preferably mediated by PDE4enzyme, comprising administering 1 mg, 5 mg, 10 mg, 30 mg, 40 mg, 50 mg,60 mg, 70 mg, 90 mg, 100 mg, 120 mg, 150 mg, or 200 mg of the crystalform II of the compound as disclosed herein to a subject in needthereof.

Methods of Administration

At least one of the crystal form II of the compound of the presentdisclosure or the pharmaceutical compositions comprising at least one ofthe crystal form II of the compound of the present disclosure may beadministered to the patient by any suitable means and/or by any meansthat topically delivers the crystal form II of the compound of thepresent disclosure. Non-limiting examples of methods of administrationinclude, among others, (a) administration though oral pathways, whichadministration includes administration in capsule, tablet, granule,spray, syrup, or other such forms; (b) administration through non-oralpathways such as rectal, vaginal, intraurethral, intraocular,intranasal, or intraauricular, which administration includesadministration as an aqueous suspension, an oily preparation or the likeor as a drip, spray, suppository, salve, ointment or the like; (c)administration via injection, subcutaneously, intraperitoneally,intravenously, intramuscularly, intradermally, intraorbitally,intracapsularly, intraspinally, intrasternally, or the like, includinginfusion pump delivery; (d) administration locally such as by injectiondirectly in the renal or cardiac area, e.g., by depot implantation; aswell as (e) administration topically; as deemed appropriate by those ofskill in the art for bringing the crystal form II of the compound of thepresent disclosure into contact with living tissue. For example,transdermal administration, which includes administration in anointment, cream, gel, aerosol, suspension, emulsion, or other suchforms.

The most suitable route depends on the nature and severity of thecondition to be treated. A person having ordinary skill in the art alsoknows determination of methods of administration (buccal, intravenous,inhalation subcutaneous, rectal and the like), dosage form, suitablepharmaceutical excipients and other events regarding delivering thecrystal forms of the compound to a subject in need thereof.

Pharmaceutical compositions suitable for administration includecompositions where the active ingredients are contained in an amounteffective to achieve its intended purpose. The therapeutically effectiveamount of the crystal forms of the compound disclosed herein required asa dose will depend on the route of administration, the type of animal,including human, being treated, and the physical characteristics of thespecific animal under consideration. The dose can be tailored to achievea desired effect, but will depend on such factors as weight, diet,concurrent medication and other factors which those skilled in themedical arts will recognize. More specifically, a therapeuticallyeffective amount means an amount of crystal form of the compoundeffective to prevent, alleviate or ameliorate symptoms of disease orprolong the survival of the subject being treated. Determination of atherapeutically effective amount is well within the capability of thoseskilled in the art, especially in light of the detailed disclosureprovided herein.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight and mammalian species treated,the particular crystal forms of the compounds employed, and the specificuse for which these crystal forms of the compounds are employed. Thedetermination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine pharmacological methods. Typically,human clinical applications of products are commenced at lower dosagelevels, with dosage level being increased until the desired effect isachieved. Alternatively, acceptable in vitro studies can be used toestablish useful doses and routes of administration of the compositionsidentified by the present methods using established pharmacologicalmethods.

In non-human animal studies, applications of potential products arecommenced at higher dosage levels, with dosage being decreased until thedesired effect is no longer achieved or adverse side effects disappear.The dosage may range broadly, depending upon the desired affects and thetherapeutic indication. Typically, dosages may be between about 10 μg/kgand 1000 mg/kg body weight, in some embodiments, between about 100 μg/kgand 300 mg/kg body weight. Alternatively, dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art.

The exact formulation, route of administration and dosage for thepharmaceutical compositions of the present disclosure can be chosen bythe individual physician in view of the patient's condition. Typically,the dose range of the composition administered to the patient can befrom about 0.5 to 1000 mg/kg of the patient's body weight. The dosagemay be a single one or a series of two or more given in the course ofone or more days, as is needed by the patient. In instances where humandosages for compounds have been established for at least some condition,the present disclosure will use those same dosages, or dosages that arebetween about 0.1% and 500%, in some embodiments, between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompounds, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Although the exact dosage will be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.1 mg and 2000 mg of each active ingredient, insome embodiments, between 1 mg and 2000 mg, e.g. 5 to 1500 mg. In otherembodiments, an intravenous, subcutaneous, or intramuscular dose of eachactive ingredient of between 0.01 mg and 1000 mg, in some embodiments,between 0.1 mg and 1000 mg, e.g. 1 to 800 mg is used. In cases ofadministration of a pharmaceutically acceptable salt, dosages may becalculated as the free base. In some embodiments, the composition isadministered 1 to 4 times per day. Alternatively, the compositions ofthe disclosure may be administered by continuous intravenous infusion,in some embodiments, at a dose of each active ingredient up to 2000 mgper day. As will be understood by those of skill in the art, in certainsituations it may be necessary to administer the compounds disclosedherein in amounts that exceed, or even far exceed, the above-stateddosage range in order to effectively and aggressively treat particularlyaggressive diseases or infections. In some embodiments, the compoundswill be administered for a period of continuous therapy, for example fora week or more, or for months or years.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, in some embodiments, between30-90% and in some embodiments, between 50-90%.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and in some embodiments, human, cellline. The results of such studies are often predictive of toxicity inanimals, such as mammals, or more specifically, humans. Alternatively,the toxicity of particular compounds in an animal model, such as mice,rats, rabbits, or monkeys, may be determined using known methods. Theefficacy of a particular compound may be established using severalrecognized methods, such as in vitro methods, animal models, or humanclinical trials. Recognized in vitro models exist for nearly every classof condition, including but not limited to cancer, cardiovasculardisease, and various immune dysfunction. Similarly, acceptable animalmodels may be used to establish efficacy of chemicals to treat suchconditions. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, and route of administration, and regime. Of course, humanclinical trials can also be used to determine the efficacy of a compoundin humans.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the State Food and Drug Administration or the U.S. Food and DrugAdministration for prescription drugs, or the approved product insert.Compositions comprising a compound of the disclosure, a stereoisomerthereof or a pharmaceutically acceptable salt thereof formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having characteristic peaks atdiffraction angles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°,23.1° and 24.4° in an X-ray powder diffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity has characteristic peaks at diffractionangles 2θ of about 8.3°, 13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and24.4° in an X-ray powder diffraction (XRPD) pattern under CuKαradiation.

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having characteristic peaks atdiffraction angles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°,18.7±0.2°, 21.6±0.2°, 23.1±0.2° and 24.4±0.2° in an X-ray powderdiffraction (XRPD) pattern.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity has characteristic peaks at diffractionangles 2θ of 8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°,21.6±0.2°, 23.1±0.2° and 24.4±0.2° in an X-ray powder diffraction (XRPD)pattern under CuKα radiation.

In another aspect, the present disclosure relates to crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, wherein diffraction angle 2θ, crystalplane spacing d and relative intensity of diffraction peak in an X-raypowder diffraction (XRPD) pattern are about as follows:

2θ (°) Crystal Plane Spacing d (Å) Intensity (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In some embodiments, diffraction angle 20, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern under CuKα radiation of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity are about as follows:

2θ (°) Crystal Plane Spacing d (Å) Intensity (%) 8.3 10.6 83.5 13.8 6.457.1 14.5 6.1 60.4 16.8 5.3 100.0 18.7 4.8 56.0 21.6 4.1 63.7 23.1 3.998.9 24.4 3.7 71.4

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, wherein diffraction angle 2θ, crystalplane spacing d and relative intensity of diffraction peak in an X-raypowder diffraction (XRPD) pattern are about as follows:

2θ (°) Crystal Plane Spacing d (Å) Intensity (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In some embodiments, diffraction angle 2θ, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern under CuKα radiation of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity are about as follows:

2θ (°) Crystal Plane Spacing d (Å) Intensity (%) 8.3 10.6 83.5 11.9 7.519.8 13.8 6.4 57.1 14.5 6.1 60.4 15.1 5.9 29.7 16.8 5.3 100.0 17.2 5.145.1 17.9 5.0 23.1 18.7 4.8 56.0 19.3 4.6 31.9 20.2 4.4 19.8 21.6 4.163.7 22.3 4.0 17.6 23.1 3.9 98.9 23.9 3.7 25.3 24.4 3.7 71.4 25.8 3.527.5 27.5 3.2 26.4 30.4 2.9 23.1

In yet another aspect, the present disclosure relates to crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity, having an X-ray powder diffraction (XRPD)pattern substantially as shown in FIG. 1.

In some embodiments, the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewith PDE4 inhibitory activity has an X-ray powder diffraction (XRPD)pattern under CuKα radiation substantially as shown in FIG. 1.

In another aspect, the present disclosure relates to a method forreducing PDE4 activity, comprising administering a therapeuticallyeffective amount of crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideor a therapeutically effective amount of a pharmaceutical compositioncomprising crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideto a subject in need thereof, wherein the crystal form I hascharacteristic peaks at diffraction angles 2θ of about 8.3°, 13.8°,14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.

The present disclosure will hereinafter be explained in detail in orderto better understand the aspects of the present application and itsadvantages. However, it is to be understood that the following examplesare non-limiting and merely illustrative of certain embodiments of thepresent application.

EXAMPLES Preparation Examples Preparation of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideAbbreviations

CDI: 1,1′-carbonyldiimidazole;

DCM: dichloromethane;

THF: tetrahydrofuran;

TFA: trifluoroacetic acid;

DMAP: 4-(N,N-dimethylamino)pyridine;

TEA: triethylamine;

DMF: N,N-dimethylformamide;

DMSO: dimethylsulfoxide;

HOBt: 1-hydroxybenzotriazole;

DCC: N,N-dicyclohexyl carbondiimide;

TBFA: tetrabutylammonium fluoride;

EDC.HCl: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride;

Fmoc: 9-fluorenylmethoxycarbonyl;

MOM: methoxymethyl;

MEM: methoxy ethoxy methyl;

MTM: methylthiomethyl;

SEM: 2-(trimethylsilyl) ethoxy methyl;

TMSE: 2-(trimethylsilyl)ethyl;

DIC: N,N′-diisopropyl carbodiimide;

HOAt: 1-hydroxy-7-azobenzotriazole;

BOP: (benzotriazole-1-yl-oxy-tri-(dimethylamino) phosphonium hexafluorophosphate);

Cl-HOBt: 6-chloro-1-hydroxy benzotriazole;

DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-phentriazine-4-one;

HATU:bis(dimethylamino)methylene-triazole[4,5-B]pyridine-3-oxidehexafluorophosphate;

HBTU: benzotriazole-N,N,N′,N′-tetramethylureahexafluorophosphate;

HCTU: 6-chlorobenzotriazole-1,1,3,3-tetramethylureahexafluorophosphate;

HOOBt: 3-hydroxy-1,2,3-phentriazine-4(3H)-one;

PyBOP: hexafluorophosphoric acid benzotriazole-1-yl-oxytripyrrolidinylphosphine;

TATU: O-(7-azobenzotriazole-1-yl)-N,N,N′,N′-tetramethylureatetrafluoroborate;

TBTU: O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethylureatetrafluoroborate;

OMS: methanesulfonic acid ester;

OTS: p-toluenesulfonic acid ester.

Compound 1 4-methoxy-3-ethoxybenzaldehyde

To a 500 ml three-neck flask equipped with a mechanical stirrer and aninert gas tube were added 30.5 g of isovanillin, 55.2 g of potassiumcarbonate, 49.9 g of iodoethane and 140 mL of DMF. The mixture wasstirred overnight at the room temperature. The mixture was poured into1400 mL of water, and then the resultant mixture was extracted withethyl acetate (600 mL×2). The ethyl acetate layers were combined. Theorganic phase was washed with saturated Na₂CO₃ (200 mL×3), 200 mL ofwater and 200 mL saturated NaCl, dried over anhydrous MgSO₄, andfiltered. The solvent was evaporated to give a straw yellow solid. Thesolid was recrystallized with a mixed solvent of ethyl acetate andpetroleum ether (1:4) to give a white needle crystal (32.9 g). MS (m/z):181 [M+1]⁺.

Compound 21-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-N-(trimethylsilyl)ethylamine

To a 500 mL three-neck flask equipped with a magnetic stirrer and aninert gas tube were added 3.7 g of dimethyl sulfone and 160 mL of THF.The mixture was cooled to −78° C. and 22 mL of n-butyl lithium (2.2 Mn-hexane solution) was added dropwise in the mixture. After the additionthe mixture was maintained at −78° C. and stirred for 30 min to obtainA. In a 250 mL three-neck flask equipped with a magnetic stirrer and aninert gas tube was added 7.1 g of compound 1a. The flask was cooled inan ice-salt bath. 43 mL of lithium bis-(trimethylsilyl) amide (1.06 MTHE solution) was added dropwise in the flask. After the addition themixture was stirred for 15 min, and then 10 mL solution of borontrifluoride in diethyl ether was added dropwise to the mixture. Theresultant mixture was stirred for 5 min to obtain B. B was transferredinto A. The mixture was warmed slowly to the room temperature (overabout 1.5 hours). The reaction was quenched with 200 mL of 1.6N K₂CO₃solution. The mixture was stirred for 30 min and then separated. Theaqueous layer was extracted with ethyl acetate (200 mL×3). All theorganic layers were combined. The resultant organic phase was washedwith 200 mL saturated NaCl, dried over anhydrous MgSO₄ and filtered. Thesolvent was evaporated to give 10 g of a straw yellow foam solid.

Compound 3 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine

To a 500 mL of single-neck flask equipped with a magnetic stirrer wereadded 10 g of compound 2, 100 mL of diethyl ether and 100 ml of 4N HCl.The mixture was stirred for 30 min at the room temperature andseparated. The organic layer was extracted with 4N HCl (100 mL×3). Theaqueous layers were combined. The pH of the aqueous phase was adjustedto 12 with 4N sodium hydroxide in an ice bath. The resultant mixture wasextracted with ethyl acetate (200 mL×3). The organic layers werecombined. The organic phase was washed with 200 mL of saturated NaCl,dried over anhydrous MgSO₄ and filtered. The solvent was evaporated. 1.5g of a white solid was given after purified with column chromatography.

¹H NMR (CDCl₃): δ 6.93-6.84 (m, 3H), 4.60 (d, 1H, J=8 Hz), 4.12 (q, 2H,J=4 Hz), 3.87 (s, 3H), 3.37-3.21 (m, 2H), 2.92 (s, 3H), 1.86 (s, 2H),1.48 (t, 3H, J=4 Hz); MS (m/z): 274 [M+1]⁺; Chiral HPLC(isopropanol/n-hexane/diethylamine=35/65/0.1, Chiralce® OJ-H column,250×4.6 mm, 1.0 mL/min, @234 nm): 15.2 min (R-isomer, 49.8%), 17.3 min(S-isomer, 50.2%).

Compound 4a(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamineN-acetyl-L-valine Salt

To a 100 mL of single-neck flask equipped with a magnetic stirrer, areflux-condenser and an inert gas tube were added 6.920 g of compound 3,2.418 g of N-acetyl L-valine and 50 mL of anhydrous methanol. Themixture was refluxed in an oil-bath for 1 hour, stirred for 3 hours atthe room temperature, and filtered in vacuo to give a white solid. Thewhite solid was added in 25 mL of anhydrous methanol. The resultantmixture was refluxed for 1 hour, stirred at the room temperature for 3hours, and filtered in vacuo to give 6.752 g of a white solid.

Compound 4b(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine

To a 250 mL of single-neck flask equipped with a magnetic stirrer wereadded 6.752 g of compound 4a, 150 mL of dichloromethane and 150 ml ofwater. To the mixture was added dropwise 5% sodium hydroxide aqueoussolution in an ice bath to adjust pH to 11. The resultant mixture wasseparated. The aqueous layer was extracted with 150 mL ofdichloromethane. The dichloromethane layers were combined. The organicphase was washed with 100 ml of saturated NaCl, dried over anhydrousMgSO₄, and filtered. The solvent was evaporated to give 2.855 g of awhite solid (99.0% ee). MS (m/z): 274 [M+1]⁺; Chiral HPLC(isopropanol/n-hexane/diethylamine=35/65/0.1, Chiralcel® OJ-H column,250×4.6 mm, 1.0 mL/min, @234 nm): 15.2 min (R-isomer, 0.5%), 17.3 min(S-isomer, 99.5%).

Compound 5 3,4-dicyanothiophene

To a 2000 mL of three-neck flask equipped with a magnetic stirrer, areflux-condenser and an inert gas tube were added 96.8 g of3,4-dibrominethiophene, 104 g of cuprous cyanide and 100 mL of driedDMF. The mixture was heated at reflux for 4 hours and cooled to the roomtemperature. To the reaction mixture was added a solution of 400 g ofFeCl₃.6H₂O in 700 mL of 1.7N hydrochloric acid. The reaction solutionwas maintained at 60° C.-70° C. for 30 min. 500 mL of DCM was added tothe reaction solution after sufficiently cooled. The resultant mixturewas divided into several portions. Each portion is 300 mL and extractedwith DCM (300 mL×2). All DCM layers were combined. The extract wasdivided into several portions. Each portion is 600 mL and washed with 6Nof hydrochloric acid (50 mL×2), water, saturated Na₂CO₃ aqueous solutionand saturated saline solution sequentially, dried over anhydrous MgSO₄,and filtered. The solvent was evaporated to give a yellow solid. Theyellow solid was washed with a mixed solvent of ethyl acetate andpetroleum ether (1:1) and filtered to give 21 g of a white solid. ¹H NMR(CDCl₃): δ 8.07 (s, 2H).

Compound 6 thiophene-3,4-dicarboxylic Acid

To a 500 mL of round-bottom flask equipped with an electromagneticstirrer and a reflux-condenser were added 15.978 g of compound 5, 43.997g of potassium hydroxide and 174 mL of ethylene glycol. The mixture wasrefluxed for 4 hours. After cooling, 350 mL of water was added to thereaction mixture. The resultant mixture was extracted with diethyl ether(100 mL×2). The diethyl ether layers were discarded. An excess amount ofconcentrated hydrochloric acid was added to the aqueous layer in an icebath to give a white precipitate. The white precipitate was filtratedand the solid was dissolved in diethyl ether (about 2000 mL). Thefiltrate was extracted with diethyl ether (300 mL×3). All diethyl etherlayers were combined. The organic phase was dried over anhydrous MgSO₄and filtered. The solvent was evaporated to give 15 g of a white solid.The white solid was recrystallized with water. ¹H NMR (DMSO-d₆): δ 10.35(brs, 2H), 8.17 (s, 2H); MS (m/z): 171 [M−1]⁺.

Compound 7 thiophene[3,4-c]furan-1,3-diketone

To a 250 mL of round-bottom flask equipped with an electromagneticstirrer, a reflux-condenser and a drying tube were added 15 g ofcompound 6 and 120 mL of acetic anhydride. The mixture was refluxed for3 hours. The solvent was evaporated to give 13 g of a brown solid.

Compound 8 2-nitrothiophene-3,4-dicarboxylic Acid

To a 250 mL of round-bottom flask equipped with an electromagneticstirrer and a drying tube was added 40 ml of fuming nitric acid (contentof 95%). The flask was cooled to 0° C.-5° C. with an ice bath. 10 g ofcompound 7 was added portionwise (1 g for each portion). After additionthe mixture was reacted for 30 min at the current temperature (a yellowsolid separated out). The reaction mixture was poured into 80 g of anice-water mixture. The resultant mixture was extracted with ethylacetate (100 mL×3). All ethyl acetate layers were combined. The organicphase was washed sequentially with 50 mL×2 of water and saturated salinesolution, dried over anhydrous MgSO₄ and filtered. The solvent wasevaporated to give 10 g of a yellow solid. MS (m/z): 216 [M−1]⁺.

Compound 9 4-nitrothiophene[3,4-c]furan-1,3-diketone

To a 250 mL of round-bottom flask equipped with an electromagneticstirrer, a reflux-condenser and a drying tube were added 10 g ofcompound 8 and 100 ml of acetic anhydride. The mixture was refluxed for3 hours. The solvent was evaporated to give 9 g of a brown solid.

Compound 10(S)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketone

To a 250 mL of round-bottom flask equipped with an electromagneticstirrer and a drying tube were added 1.99 g of compound 9, 2.73 g of(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethylamine (compound4b) and 100 mL of THF. The mixture was stirred overnight at the roomtemperature. 1.944 g of CDI was added. The resultant mixture wasrefluxed in an oil-bath for 2 hours. The mixture was cooled to the roomtemperature in the open air. 200 mL of ethyl acetate and 150 mL of waterwere added. The mixture was extracted and separated. The organic layerwas washed with 100 mL of 0.5N HCl, 100 mL of saturated NaCl, then driedover anhydrous MgSO₄ and filtered. The solvent was evaporated. 3.485 gof a light yellow solid was given after purified with columnchromatography. MS (m/z). 453 [M−1]⁺.

Compound 11(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione

To a 250 mL of round-bottom flask equipped with an electromagneticstirrer, a reflux-condenser and a drying tube were added 2.27 g of(S)-1-nitro-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-diketoneand 100 mL of THF. The mixture was heated at reflux. 1.4 g of reductivepowdery iron was added. The resultant mixture was refluxed for 2 hoursand filtered in vacuo. The filtrate was evaporated. 200 mL of ethylacetate and 150 mL of water was added. The mixture was extracted andseparated. The organic layer was washed with 100 mL of water, 100 mL ofsaturated NaCl, then dried over anhydrous MgSO₄ and filtered. Thesolvent was evaporated. 1.53 g of a yellowish-brown solid was givenafter purified with column chromatography. MS (m/z): 425 [M+1]⁺.

Compound 12(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thiophene[3,4-c]pyrrole-1-yl)acetamide

Method I: To a 50 mL of round-bottom flask equipped with anelectromagnetic stirrer, a reflux-condenser and a drying tube were added0.1 g of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dione,0.005 g of DMAP and 10 mL of acetic anhydride. The mixture was heated to60° C. and stirred for 6 hours. The solvent was evaporated. 0.022 g oftitle compound was given after purified with column chromatography.

Method II: To a 50 mL of round-bottom flask equipped with anelectromagnetic stirrer, a reflux-condenser and a drying tube were added0.1 g of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-5H-thiophene[3,4-c]pyrrole-4,6-dioneand 5 mL of pyridine. 0.2 mL of acetylchloride was added dropwise in anice bath and stirred for 1 hour at the room temperature. The solvent wasevaporated. 50 mL of ethyl acetate and 20 mL of water were added. Themixture was extracted and separated. The organic layer was washed with20 mL of 2N HCl, 20 mL of saturated NaCl, then dried over anhydrousMgSO₄ and filtered. The solvent was evaporated. 0.083 g of titlecompound was given after purified with column chromatography. MS (m/z):465 [M−1]⁺. Chiral HPLC (anhydrousalcohol/n-hexane/diethylamine=40/60/0.1, Chiralcel® OJ-H column, 250×4.6mm, 1.0 mL/min, @230 nm): 9.8 min (R-isomer, 1.2%), 13.8 min (S-isomer,98.8%). ¹H NMR (CDCl3): δ 9.27 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 7.05(s, 1H), 6.81 (d, 1H, J=6 Hz), 5.81 (dd, 1H, J=3 Hz, J=7 Hz), 4.54 (dd,1H, J=8 Hz, J=11 Hz), 4.08 (q, 2H, J=3 Hz), 3.84 (s, 3H), 3.73 (dd, 1H,J=8 Hz, J=11 Hz), 2.86 (s, 3H), 2.27 (s, 3H), 1.45 (t, 3H, J=5 Hz).

Example 1 Preparation of Crystal Form II

0.356 g of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewas dissolved in 40 mL of ethyl acetate. The mixture was stirred at theroom temperature until completed dissolved. After filtered, the filtratewas heated to 60° C. and evaporated at the same temperature under theatmospheric pressure to precipitate crystalline powders. The powderswere filtered and dried in vacuo to give 0.190 g of white powder solid(yield: 53%), i.e., crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide.

Example 2 X-Ray Powder Diffraction (XRPD)

The experimental parameters of X-ray powder diffraction (XRPD) were asfollows: X-ray powder diffraction (XRPD) patterns were obtained byBruker D8 Advance X-ray powder diffractometer with Cu anode (40 mA, 45kV). The scanning range was 2θ=2-40°, the step size was 0.02° and thescanning rate was 8°/min.

The X-ray powder diffraction (XRPD) pattern of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process in Example 1 was shown in FIG. 1.

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehas characteristic peaks at diffraction angles 2θ of 8.3±0.2°,11.9±0.2°, 13.8±0.2°, 14.5±0.2°, 15.1±0.2°, 16.8±0.2°, 17.2±0.2°,17.9±0.2°, 18.7±0.2°, 19.3±0.2°, 20.2±0.2°, 21.6±0.2°, 22.3±0.2°,23.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.8±0.2°, 27.5±0.2° and 30.4±0.2° inan X-ray powder diffraction (XRPD) pattern but has no obviousdiffraction peak at other angles.

Example 3 Differential Scanning Calorimetry (DSC) Test

The experimental parameters of differential scanning calorimetry (DSC)were as follows: the heat absorption and release information of theheating of a sample during heating process was obtained by Seiko SII6220 differential scanning calorimeter (DSC). The heating rate was 10°C./min. Nitrogen was used as protection gas.

The DSC curve of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process in Example 1 was shown in FIG. 2.

The crystal form II had an endothermic melting peak at 174.2±6° C. (peakmelting point) during the heating process.

Example 4 Thermogravimetric Analysis (TGA) Test

The experimental parameters of thermogravimetric analysis method (TGA)were as follows: the weight loss information of a sample during heatingprocess was obtained with Seiko SII 6200 thermogravimetric detector(TG). The heating rate was 10° C./min. Nitrogen was used as protectiongas.

The TGA curve of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process in Example 1 was shown in FIG. 3.

The weight loss of the crystal formal II was 0.3% when the crystal formII was heated to melt. No heat absorption or release peak was shownbefore melting. This demonstrated that 0.3% of weight loss was adsorbedwater or solvent. The crystal form II was neither a hydrate nor asolvate.

Example 5 Infrared (IR) Spectroscopy

The experimental parameters of infrared were as follows: PerkinElmer,Spectrum B65.

The infrared (IR) spectroscopy of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process in Example 1 was shown in FIG. 4.

The position and intensity of absorption peak of the crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process in Example 1 in an infrared (IR)spectroscopy were about as follows:

Position of Intensity of Absorption Peak (cm⁻¹) Absorption Peak (%)3453.2 70.26 3241.43 48.73 3180.17 71.75 3083.24 76.81 3027.45 63.763006.17 61.87 2984.61 66.79 2957.88 66.9 2929.86 60.24 2874.13 72.922838.3 73.97 1762.16 35.25 1711.28 6.93 1696.91 16.68 1589.87 17.991556.49 32.02 1519.41 25.37 1501.04 44.56 1474.83 62.39 1462.27 64.911444.23 64.41 1434.62 58.52 1392.39 41.14 1370.64 49.6 1334.38 20.751290.88 11.9 1261.44 22.72 1239.78 16.73 1186.33 72.49 1165.47 65.761139.31 19.78 1090.26 28.34 1041.96 50.12 1024.97 51.39 1013.68 54.36987.29 69.86 974.97 54.3 893.33 61.77 884.21 86.94 853.9 63.5 821.4174.9 807.59 77.16 772.11 68.12 763.87 64.75 733.78 56.35 717.63 35.54698.77 65.19 645.374 65.19 605.85 69.96 582.92 80.93 560.18 81.03 538.8163.92 526.24 69.09 511.55 77.6 485.9 62.86 453.09 63.17

Example 6 High Temperature Stability

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process of Example 1 was placed at 40° C.(high temperature). After 1 month, liquid chromatogram and DSC weretested. The results of relevant substances and crystal form were shownin Table 1. The results demonstrated that the crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehad good stability under high temperature conditions.

TABLE 1 Test Results of Stability at 40° C. Relevant Relevant CrystalOriginal Substance Substance Form Crystal Contents at Storage Contentsafter 1 after 1 Form Day 0 (%) Condition Month (%) Month II 0.10 40° C.0.12 II

Example 7 Accelerated Stability

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process of Example 1 was placed in a stabilitytext box at 40° C. and Rh=75%. After 1 month, liquid chromatogram andDSC were tested. The results of relevant substances and crystal formwere shown in Table 2. The results demonstrated that the crystal form IIof(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehad good stability under high-temperature and high-humidity conditions.

TABLE 2 Test Results of Stability under Accelerated Conditions RelevantOriginal Relevant Substance Substance Crystal Form Crystal Contents atStorage Contents after after 1 Form Day 0 (%) Condition 1 Month (%)Month II 0.11 40° C. 0.11 II RH = 75%

Example 8 Illumination Stability

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process of Example 1 was placed in a 4500 luxof illumination box for 1 month. Liquid chromatogram and DSC were testedafter 1 month. The results of relevant substances and crystal form wereshown in Table 3.

TABLE 3 Test Results of Illumination Stability Relevant Relevant CrystalSubstance Substance Form Crystal Contents at Illumination Contents afterafter 1 Form Day 0(%) Conditions 1 Month (%) Month II 0.06 4500 lux 0.06II

Example 9 Grinding Stability

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process of Example 1 was ground in a glassmortar for 5 minutes. The ground samples were tested with XRPD. Theresults of crystal form were shown in Table 4. The results demonstratedthat crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidehad good grinding stability.

Table 4 Results of Grinding Stability Results Original Crystal GrindingCrystal Form after Form Manner Grinding II Grinding in a glass II mortarfor 5 minutes

Example 10 Pressure Stability

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewas pressed by tablet press machine with single punch. The diameter ofthe tablet was 6 mm and the hardness was 25-30 N. DSC test was carriedout on pressed powder. The results were shown in FIG. 5. The resultdemonstrated that the crystal form II has good stability.

Example 11 Ethanol Solution Balance Stability

0.2 g of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewas added to 10 mL of ethanol. The mixture was stirred at 25° C. for 3hours. The suspension was filtered. Wet solid was dried. X-ray powderdiffraction (XRPD) test was carried out on dry solid. The test resultsof crystal form were shown in Table 5.

TABLE 5 Test Results of Stability of Crystal in Ethanol afterEquilibrium Original Equilibrium Crystal Form Crystal TemperatureEquilibrium after Form (° C.) Time (h) Equilibrium II 25 3 II

Example 12 Hygroscopicity

Hygroscopicity of crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewas studied. Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidewas placed in a drier containing saturated ammonium chloride solution(RH=80%) until weight was balanced. The crystal form was tested withXRPD.

Crystal form II of(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideprepared according to the process of Example 1 was tested.

The results of hygroscopicity were shown in Table 6. It can beunderstood based on the test results that crystal form II hardlyabsorbed moisture. The crystal form did not change after the crystalform II was kept under 80% humidity condition.

TABLE 4 Test Results of Hygroscopicity Original Weight Moisture CrystalForm Crystal mAPI Increase Absorption after Absorbing Form (g) (g) (%)Moisture II 0.497 −0.001 0 II

In the present disclosure, relational terms, such as first and secondand the like, are used solely to distinguish one entity or operationfrom another entity or operation without necessarily requiring orimplying any such actual relationship or order between such entities oroperations.

From the foregoing it will be appreciated that, although specificembodiments of the present disclosure have been described herein forillustrative purposes, various modifications or improvements may be madeby those skilled in the art without departing from the spirit and scopeof the present disclosure. Such variations or modifications are intendedto fall within the scope of the claims appended hereto.

1. Crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamide,having characteristic peaks at diffraction angles 2θ of about 8.3°,13.8°, 14.5°, 16.8°, 18.7°, 21.6°, 23.1° and 24.4° in an X-ray powderdiffraction (XRPD) pattern.
 2. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfone)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having characteristic peaks at diffraction angles 2θ of8.3±0.2°, 13.8±0.2°, 14.5±0.2°, 16.8±0.2°, 18.7±0.2°, 21.6±0.2°,23.1±0.2° and 24.4±0.2° in an X-ray powder diffraction (XRPD) pattern.3. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, wherein diffraction angle 2θ, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern are about as follows: 2θ (°) Crystal Plane Spacing d (Å)Intensity (%) 8.3 10.6 83.5 13.8 6.4 57.1 14.5 6.1 60.4 16.8 5.3 100.018.7 4.8 56.0 21.6 4.1 63.7 23.1 3.9 98.9 24.4 3.7 71.4


4. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, wherein diffraction angle 2θ, crystal plane spacing d andrelative intensity of diffraction peak in an X-ray powder diffraction(XRPD) pattern are about as follows: 2θ (°) Crystal Plane Spacing d (Å)Intensity (%) 8.3 10.6 83.5 11.9 7.5 19.8 13.8 6.4 57.1 14.5 6.1 60.415.1 5.9 29.7 16.8 5.3 100.0 17.2 5.1 45.1 17.9 5.0 23.1 18.7 4.8 56.019.3 4.6 31.9 20.2 4.4 19.8 21.6 4.1 63.7 22.3 4.0 17.6 23.1 3.9 98.923.9 3.7 25.3 24.4 3.7 71.4 25.8 3.5 27.5 27.5 3.2 26.4 30.4 2.9 23.1


5. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having an X-ray powder diffraction (XRPD) patternsubstantially as shown in FIG.
 1. 6. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having an endothermic peak at about 174.2° C. when subjectedto thermal analysis using differential scanning calorimetry (DSC). 7.The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having a heat absorption peak at 174.2±6° C. when subjectedto thermal analysis using differential scanning calorimetry (DSC). 8.The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having a DSC curve substantially as shown in FIG. 2 whensubjected to thermal analysis using differential scanning calorimetry(DSC).
 9. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having a TGA curve substantially as shown in FIG. 3 whensubjected to thermal analysis using thermogravimetric analysis (TGA).10. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, wherein position and intensity of absorption peak of thecrystal form II in an infrared (IR) spectroscopy are about as follows:Position of Intensity of Absorpton Peak (cm⁻¹) Absorption Peak (%)3453.2 70.26 3241.43 48.73 3180.17 71.75 3083.24 76.81 3027.45 63.763006.17 61.87 2984.61 66.79 2957.88 66.9 2929.86 60.24 2874.13 72.922838.3 73.97 1762.16 35.25 1711.28 6.93 1696.91 16.68 1589.87 17.991556.49 32.02 1519.41 25.37 1501.04 44.56 1474.83 62.39 1462.27 64.911444.23 64.41 1434.62 58.52 1392.39 41.14 1370.64 49.6 1334.38 20.751290.88 11.9 1261.44 22.72 1239.78 16.73 1186.33 72.49 1165.47 65.761139.31 19.78 1090.26 28.34 1041.96 50.12 1024.97 51.39 1013.68 54.36987.79 69.86 974.97 54.3 893.33 61.77 884.21 86.94 853.9 63.5 821.4174.9 807.59 77.16 772.11 68.12 763.87 64.75 733.78 56.35 717.63 35.54698.77 65.19 645.374 65.19 605.85 69.96 582.92 80.93 560.18 81.03 538.8163.92 526.24 69.09 511.55 77.6 485.9 62.86 453.09 63.17


11. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, having an inflated (IR) spectroscopy substantially as shownin FIG.
 4. 12. The crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 that is substantially free of solvent.
 13. The crystal formII of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 that is substantially free of water.
 14. The crystal form IIof compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 that is substantially pure.
 15. The crystal form II ofcompound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 that is free of solvent and water.
 16. A pharmaceuticalcomposition, comprising the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 and a pharmaceutically acceptable carrier, diluent orexcipient.
 17. The pharmaceutical composition of claim 16, formulated astablet, solution, granule, patch, ointment, gel, capsule, aerosol orsuppository administered via parenteral, transdermal, mucosa, nasal,buccal, sublingual or oral route.
 18. A process for preparing thecrystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1, comprising crystallizing(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidein ethyl acetate to obtain the crystal form II.
 19. The process of claim18, comprising: dissolving(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamidein acetonitrile until completely dissolved; and filtering and coolingfiltrate to precipitate the crystal form I.
 20. A method for treating orpreventing a disease or condition associated with PDE4 enzyme,preferably meditated by PDE4 enzyme, comprising administering atherapeutically effective amount of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 to a subject in need thereof.
 21. The method of claim 20,wherein the subject is a mammal, preferably a human.
 22. The method ofclaim 20, wherein the disease or condition is selected from the groupconsisting of a inflammatory disease or condition, an infectious diseaseor condition, an immune disease or condition, and a cancer disease orcondition.
 23. The method of claim 20, wherein the disease or conditionis selected from the group consisting of head carcinoma, thyroidcarcinoma, neck cancer, eye cancer, skin cancer, oral cancer, throatcancer, esophagus cancer, breast cancer, bone cancer, leukemia, myeloma,lung cancer, colon cancer, carcinoma of sigmoid, rectal cancer, gastriccancer, prostate cancer, breast cancer, ovarian cancer, kidney cancer,liver cancer, pancreatic cancer, brain cancer, intestinal cancer, heartcancer, adrenal carcinoma, subcutaneous tissue cancer, lymph nodecancer, malignant melanoma, malignant glioma, HIV, hepatitis, adultrespiratory distress syndrome, bone absorption disease, chronicobstructive pulmonary disease, chronic pneumonia, dermatitis,inflammatory skin disease, atopic dermatitis, cystic fibrosis, septicshock, pyaemia, endotoxin shock, blood dynamic shock, septic diseasesyndrome, ischemia reperfusion injury, meningitis, psoriasis, fibrosisdisease, cachexia, graft rejection of graft versus host disease,autoimmunity disease, rheumatoid spondylitis, arthritis symptom (such asrheumatoid arthritis or osteoarthritis), osteoporosis, Crohn's disease,ulcerative colitis, enteritis, multiple sclerosis, systemic lupuserythematosus, erythema nodosum leprosum of leprosy (ENL), radiationdamage, asthma, oxygen enriched lung injury, microorganism infectionsand microorganism infection syndrome. 24.-28. (canceled)
 29. A methodfor reducing PDE4 activity, comprises administering a therapeuticallyeffective amount of the crystal form II of compound(S)—N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1-yl]acetamideof claim 1 to a subject in need thereof.